CD154, also known as CD40 ligand (CD40L), gp39, TNF-related activation protein (TRAP), 5c8 antigen, or T-BAM, is a trimeric transmembrane protein of the tumor necrosis factor (TNF) superfamily. CD154 is expressed in an activation-dependent, temporally-restricted manner on the surface of CD4+ T cells. CD154 is also expressed, following activation, on a subset of CD8+ T cells, basophils, mast cells, eosinophils, natural killer cells, B cells, macrophages, dendritic cells and platelets. CD154 also exists as a soluble form in the blood.
CD154 binds to CD40 on antigen-presenting cells (APC), which leads to various responses depending on the target cell type. CD40-CD154 interaction is essential for normal T-B cell interactions, including increased co-stimulation, T-cell priming, cytokine production, antibody-class switching and affinity maturation, and antibody and autoantibody production.
Disruption of the CD40/CD154 pathway via CD154 blockage has been shown to be beneficial in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), type I diabetes (T1D), and allograft rejection. In humans, mutations in either CD40 or CD154 result in hyper-IgM syndrome characterized by lack of IgG or IgA isotypes (Aruffo et al., Cell 72:291, 1993).
Anti-CD154 antibodies have been described for example in Int. Pat. Publ. Nos. WO1993/08207, WO1994/10308, WO1996/40918, WO1993/009812, WO1999/051258, WO1995/006480, WO1995/006481, WO1995/006666, WO2001/002057, WO1997/017446, WO1999/012566, WO2001/068860, WO2005/003175, WO2006/033702, WO2006/030220, WO2008/118356, WO2012/052205, WO2012/138768, WO2012/138768, WO2013/055745 and WO2013/056068.
Anti-CD154 antibodies have shown to be efficacious in the treatment of autoimmune diseases in humans. However, thromboembolism due to platelet activation observed upon treatment prohibited continued clinical development. Engagement of FcγRIIa on platelets has been shown to be causative for platelet activation by the anti-CD154 antibody 5c8 (Xie et al., J Immunol 192:4083-4092, 2014).
Thus, there is a need for additional anti-CD154 antibodies with improved safety and efficacy profiles.